Pharmacological actions of the bioactive compounds of Epimedium on the male reproductive system: current status and future perspective.

ABSTRACT: Compounds isolated from Epimedium include the total flavonoids of Epimedium, icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium, its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.

Micropeptides: potential treatment strategies for cancer.

Some noncoding RNAs (ncRNAs) carry open reading frames (ORFs) that can be translated into micropeptides, although noncoding RNAs (ncRNAs) have been previously assumed to constitute a class of RNA transcripts without coding capacity. Furthermore, recent studies have revealed that ncRNA-derived micropeptides exhibit regulatory functions in the development of many tumours. Although some of these micropeptides inhibit tumour growth, others promote it. Understanding the role of ncRNA-encoded micropeptides in cancer poses new challenges for cancer research, but also offers promising prospects for cancer therapy. In this review, we summarize the types of ncRNAs that can encode micropeptides, highlighting recent technical developments that have made it easier to research micropeptides, such as ribosome analysis, mass spectrometry, bioinformatics methods, and CRISPR/Cas9. Furthermore, based on the distribution of micropeptides in different subcellular locations, we explain the biological functions of micropeptides in different human cancers and discuss their underestimated potential as diagnostic biomarkers and anticancer therapeutic targets in clinical applications, information that may contribute to the discovery and development of new micropeptide-based tools for early diagnosis and anticancer drug development.

LC-MS/MS platform-based serum untargeted screening reveals the diagnostic biomarker panel and molecular mechanism of breast cancer.

BACKGROUND: Breast cancer (BC), the most common form of malignant cancer affecting women worldwide, was characterized by heterogeneous metabolic disorder and lack of effective biomarkers for diagnosis. The purpose of this study is to search for reliable metabolite biomarkers of BC as well as triple-negative breast cancer (TNBC) using serum metabolomics approach. METHODS: In this study, an untargeted metabolomics technique based on ultra-high performance liquid chromatography combined with mass spectrometry (UHPLC-MS) was utilized to investigate the differences in serum metabolic profile between the BC group (n = 53) and non-BC group (n = 57), as well as between TNBC patients (n = 23) and non-TNBC subjects (n = 30). The multivariate data analysis, determination of the fold change and the Mann-Whitney U test were used to screen out the differential metabolites. Additionally, machine learning methods including receiver operating curve analysis and logistic regression analysis were conducted to establish diagnostic biomarker panels. RESULTS: There were 36 metabolites found to be significantly different between BC and non-BC groups, and 12 metabolites discovered to be significantly different between TNBC and non-TNBC patients. Results also showed that four metabolites, including N-acetyl-D-tryptophan, 2-arachidonoylglycerol, pipecolic acid and oxoglutaric acid, were considered as vital biomarkers for the diagnosis of BC and non-BC with an area under the curve (AUC) of 0.995. Another two-metabolite panel of N-acetyl-D-tryptophan and 2-arachidonoylglycerol was discovered to discriminate TNBC from non-TNBC and produced an AUC of 0.965. CONCLUSION: This study demonstrated that serum metabolomics can be used to identify BC specifically and identified promising serum metabolic markers for TNBC diagnosis.

Multifunctional nanoplatform based on tetragonal BaTiO3-Au@polydopamine for computed tomography imaging-guided photothermal synergistic and enhanced piezocatalytic cancer therapy.

Non-centrosymmetric tetragonal barium titanate nanocrystals have the potential to serve as piezoelectric catalysts in cancer therapy. When exposed to ultrasound irradiation, BaTiO3 can generate reactive oxygen species with a noninvasive and deep tissue-penetrating approach. However, the application of BaTiO3 in cancer nanomedicine is limited by their biosafety, biocompatibility, and dosage efficiency. To explore the potential application of BaTiO3 in nanomedical cancer treatment, we introduced ultra-small Au nanoparticles onto the surface of BaTiO3 to enhance the piezoelectric catalytic performance. Additionally, we also coated the BaTiO3 with polydopamine to improve their biosafety and biocompatibility. This led to the preparation of a novel multifunctional BaTiO3-based nanoplatform called BTAPs. In vitro and in vivo experiments demonstrated that the incorporation of Au dopants and polydopamine coating successfully improved the piezoelectric catalysis properties and biocompatibility of BaTiO3. Compared with unmodified BaTiO3, BTAPs achieved a similar piezoelectric catalytic effect at a low dose (0.3 mg ml-1 in vitro and 10 mg kg-1 in vivo). Moreover, BTAPs also exhibited enhanced properties in computed tomography imaging and photothermal effects in vivo. Therefore, BTAPs offer valuable insights into the advantages and limitations of piezoelectric catalytic nanomedicine in cancer treatment.

Protein-coated cobalt oxide-hydroxide nanospheres deliver photosensitizer IR780 iodide for near-infrared light-triggered photodynamic/photothermal/chemodynamic therapy against colon cancer.

Phototherapy has garnered worldwide attention for its minimal invasiveness, controllability, and spatial selectivity in treating cancer. One promising approach involves the use of near-infrared dye IR780, which demonstrates both photodynamic therapy (PDT) and photothermal therapy (PTT) effects under 808 nm laser irradiation. However, this hydrophobic dye's toxicity and limited tumor targeting ability severely hamper its suitability for cancer applications. Herein, a biocompatible nanoplatform CoOOH-IR780@BSA (CoIRB) is developed to efficiently deliver IR780 and provide multi-mode treatments for colon tumors. Due to the nanocarrier coating, CoIRB nanoparticles demonstrated reliable dispersion and stability, and their biotoxicity was substantially reduced for safer blood circulation, which overcame the biological barrier of IR780. The nanoplatform has also shown considerable results in phototherapy in vivo and in vitro experiments, with successful inhibition of MC38 tumor growth through intravenous administration. Additionally, the introduction of cobalt ions could induce Fenton-like reactions to activate the production of toxic hydroxyl radicals (˙OH), exerting an assisted chemodynamic therapy (CDT) effect. Notably, these nanodrugs also exhibited potential as scavengers of reductive glutathione (GSH) and hydrogen sulfide (H2S), leading to amplifying oxidative damage of reactive oxygen species (ROS). Overall, the versatile therapeutic platform, CoIRB, has opened up considerable prospects as a biotherapeutic option for combining PDT/PTT/CDT against colon cancer.

Novel lipidomes profile and clinical phenotype identified in pneumoconiosis patients.

BACKGROUND: Pneumoconiosis is a group of occupational lung diseases caused by the inhalation of mineral dust in the lungs, leading to lung dysfunction. Patients with pneumoconiosis are usually accompanied by weight loss, which suggests a lipid metabolism disorder. Recent progress in lipidomics uncovered detailed lipid profiles that play important roles in respiratory diseases, such as asthma, lung cancer and lung injury. The purpose of this study was to shed light on the different expression of lipidome between pneumoconiosis and healthy, hoping to bring new ideas for the diagnosis and treatment of pneumoconiosis. METHODOLOGY: This non-matching case-control study was performed among 96 subjects (48 outpatients with male pneumoconiosis and 48 healthy volunteers), data of clinical phenotypes were recorded, and plasma biochemistry (lipidomic profiles) was tested for both pneumoconiosis patients and healthy controls. A total of 426 species in 11 lipid classes were analyzed by high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-QqQ-MS) for the cases and controls. We also analyzed the correlation of lipid profiles with clinical phenomes from pneumoconiosis patients by expression quantitative trait locus (eQTL) model to evaluate trans-nodules between lipidomic profiles and clinical phenomes. All visually re-checked data were analyzed using appropriate statistical tools (t-test or one-way ANOVA test) on SPSS. RESULTS: Compared with healthy people, 26 significantly increased (> 1.5-fold) and 30 decreased lipid elements (< 2/threefold) in patients with pneumoconiosis were identified (P values all < 0.05). The majority of those elevated lipid elements were phosphatidylethanolamines (PEs), and the minority were free fatty acids (FFAs), while phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) declined in pneumoconiosis. Clinical trans-omics analyses demonstrated that phenomes in pneumoconiosis connections with multiple lipids, which showed that pH, lung function, mediastinal lymph node calcification, and complication were highly correlated with lipid elements. Furthermore, up-regulated PE was corresponded to pH, smoking history and mediastinal lymph node calcification. PC was corresponded to dust exposure history, BMI and mediastinal lymph node calcification. CONCLUSION: We found altered lipid panels between male pneumoconiosis patients and healthy people by qualitatively and quantitatively measured plasma lipidomic profiles. The trans-omic analysis between clinical phenomes and lipidomes might have the potential to uncover the heterogeneity of lipid metabolism of pneumoconiosis patients and to screen out clinically significant phenome-based lipid panels.

Naringenin: A flavanone with anti-inflammatory and anti-infective properties.

Although a growing body of research has recently shown how crucial inflammation and infection are to all major diseases, several of the medications currently available on the market have various unfavourable side effects, necessitating the development of alternative therapeutic choices. Researchers are increasingly interested in alternative medications or active components derived from natural sources. Naringenin is a commonly consumed flavonoid found in many plants, and since it was discovered to have nutritional benefits, it has been utilized to treat inflammation and infections caused by particular bacteria or viruses. However, the absence of adequate clinical data and naringenin's poor solubility and stability severely restrict its usage as a medicinal agent. In this article, we discuss naringenin's effects and mechanisms of action on autoimmune-induced inflammation, bacterial infections, and viral infections based on recent research. We also present a few suggestions for enhancing naringenin's solubility, stability, and bioavailability. This paper emphasizes the potential use of naringenin as an anti-inflammatory and anti-infective agent and the next prophylactic substance for the treatment of various inflammatory and infectious diseases, even though some mechanisms of action are still unclear, and offers some theoretical support for its clinical application.

The efficacy and safety of apatinib in patients with heavily pretreated end-stage cancer: a retrospective study.

Background: Anti-angiogenesis therapy has been a vital treatment option in a variety of cancers. Assessing the efficacy and safety of apatinib in patients with heavily pretreated end-stage cancer is essential. Methods: Thirty patients with end-stage cancer who were heavily pretreated were enrolled in this study. All patients received oral administration of apatinib (125-500 mg/d) between May 2015 and November 2016. Dose reduction or elevation was conducted based on adverse events and doctors' judgments. Results: Prior to the apatinib treatment, the enrolled patients received a median of 1.2 surgeries (range, 0-7), 1.6 sessions of radiotherapies (range, 0-6), and 10.2 cycles of chemotherapy (range, 0-60); 43.3% of patients had uncontrolled local lesions, 83.3% of patients had uncontrolled multiple metastases, and 30.0% of patients had both. After the treatment, 25 patients had valuable data, 6 (24.0%) patients achieved partial response (PR), and 12 (48.0%) patients had stable disease (SD). The disease control rate (DCR) was 72.0%. The PR and SD rates were 20.0% and 40.0%, respectively, and the DCR was 60.0% in the intent-to-treat (ITT) analysis. Meanwhile, the median progression-free survival (PFS) was 2.6 (range, 0.7-5.4) months, and the median overall survival (OS) was 3.8 (range, 1.0-12.0) months. Furthermore, the PR rate and DCR in patients with squamous cell cancer (SCC) were 45.5% and 81.8%, respectively; those in patients with adenocarcinoma (ADC) were 8.3% and 58.3%, respectively. The adverse events were generally mild. The most common adverse events were hyperbilirubinemia (53.3%), elevated transaminase (36.7%), anemia (30.0%), thrombocytopenia (30.0%), hematuria (30.0%), fatigue (26.7%), and leukopenia (20.0%). Conclusions: The results of this study demonstrate the efficacy and safety of apatinib and support the further development of apatinib as a potential treatment option for patients with heavily pretreated end-stage cancer.

The emerging role of exosomes in the development of testicular.

The mechanisms of testicular development in mammals are complex. Testis is an organ that produces sperm and secretes androgens. It is rich in exosomes and cytokines that mediate signal transduction between tubule germ cells and distal cells, promoting testicular development and spermatogenesis. Exosomes are nanoscale extracellular vesicles that transmit information between cells. By transmitting information, exosomes play an important role in male infertility diseases such as azoospermia, varicocele, and testicular torsion. However, due to the wide range of sources of exosomes, extraction methods are numerous and complex. Therefore, there are many difficulties in studying the mechanisms of exosomal effects on normal development and male infertility. Therefore, in this review, first, we introduce the formation of exosomes and methods for culturing testis and sperm. Then, we introduce the effects of exosomes on different stages of testicular development. Finally, we summarize the prospects and shortcomings of exosomes when used in clinical applications. We lay the theoretical foundation for the mechanism of the influence of exosomes on normal development and male infertility.

A double-edged sword: role of apoptosis repressor with caspase recruitment domain (ARC) in tumorigenesis and ischaemia/reperfusion (I/R) injury.

Apoptosis repressor with caspase recruitment domain (ARC) acts as a potent and multifunctional inhibitor of apoptosis, which is mainly expressed in postmitotic cells, including cardiomyocytes. ARC is special for its N-terminal caspase recruitment domain and caspase recruitment domain. Due to the powerful inhibition of apoptosis, ARC is mainly reported to act as a cardioprotective factor during ischaemia‒reperfusion (I/R) injury, preventing cardiomyocytes from being devastated by various catastrophes, including oxidative stress, calcium overload, and mitochondrial dysfunction in the circulatory system. However, recent studies have found that ARC also plays a potential regulatory role in tumorigenesis especially in colorectal cancer and renal cell carcinomas, through multiple apoptosis-associated pathways, which remains to be explored in further studies. Therefore, ARC regulates the body and maintains the balance of physiological activities with its interesting duplex. This review summarizes the current research progress of ARC in the field of tumorigenesis and ischaemia/reperfusion injury, to provide overall research status and new possibilities for researchers.

BSA-coated ß-FeOOH nanoparticles efficiently deliver the photosensitizer chlorin e6 for synergistic anticancer PDT/CDT.

Photodynamic therapy (PDT) has many exceptional advantages in cancer treatment, such as minor trauma, low toxicity side effects, and strong adaptability, effectively overcoming some obstacles of traditional therapy and providing more revolutionary opportunities for curing cancer. Chlorin e6 (Ce6) exhibits excellent singlet oxygen generation and conversion efficiency under near-infrared laser irradiation and is a promising PDT photosensitizer. However, its hydrophobicity, short half-life and lack of tumor specificity limit its in vivo anticancer application. Therefore, this work has designed and prepared a multifunctional nanoplatform, Ce6/FeOOH@BSA, to efficiently deliver Ce6. Nanoparticles exhibit excellent dispersion and stability in deionized water, PBS and DMEM, and the blood half-life is 3.98 ± 0.31 h. The nanoplatform demonstrates effective tumor targeting and accumulation, overcoming the obstacles of the biological application of Ce6. Iron ions can exert a chemodynamic therapy (CDT) effect by reacting with overexpressed H2O2 in the tumor to generate toxic hydroxyl radicals (·OH). Moreover, FeOOH nanoparticles effectively promote glutathione (GSH) consumption in tumor cells, which is conducive to accumulating reactive oxygen species (ROS). In brief, Ce6/FeOOH@BSA nanoparticles realize the targeted delivery of Ce6 and mediate synergistic PDT/CDT against tumors, broadening the biomedical application of nanomaterials.

Pyroptosis-related lncRNAs: A novel prognosis signature of colorectal cancer.

Pyroptosis is a newly discovered programmed cell death mechanism involved in tumorigenesis. Long non-coding RNAs (lncRNAs) have been implicated in colorectal cancer (CRC). However, the potential role of pyroptosis-related lncRNAs (PRLs) in CRC remains unelucidated. Therefore, we retrieved transcriptomic data of CRC patients from The Cancer Genome Atlas (TCGA). With the use of univariate and multivariate Cox proportional hazards regression models and the random forest algorithm, a new risk model was constructed based on eight PRLs: Z99289.2, FENDRR, CCDC144NL-ASL, TEX41, MNX1-AS1, NKILA, LINC02798, and LINC02381. Then, according to the Kaplan-Meier plots, the relationship of PRLs with the survival of CRC patients was explored and validated with our risk model in external datasets (Gene Expression Omnibus (GEO) databases; GEO17536, n = 177, and GSE161158, n = 250). To improve its clinical utility, a nomogram combining PRLs that could predict the clinical outcome of CRC patients was established. A full-spectrum immune landscape of CRC patients mediated by PRLs could be described. The PRLs were stratified into two molecular subtypes involved in immune modulators, immune infiltration of tumor immune microenvironment, and inflammatory pathways. Afterward, Tumor Immune Dysfunction and Exclusion (TIDE) and microsatellite instability (MSI) scores were analyzed. Three independent methods were applied to predict PRL-related sensitivity to chemotherapeutic drugs. Our comprehensive analysis of PRLs in CRC patients demonstrates a potential role of PRLs in predicting response to treatment and prognosis of CRC patients, which may provide a better understanding of molecular mechanisms underlying CRC pathogenesis and facilitate the development of effective immunotherapy.

Intrapleural infusion of tumor cell-derived microparticles packaging methotrexate or saline combined with pemetrexed-cisplatin chemotherapy for the treatment of malignant pleural effusion in advanced non-squamous non-small cell lung cancer: A double-blind, randomized, placebo-controlled study.

Background: Preclincal studies showed the promising efficacy of tumor cell-derived microparticles packaging methotrexate (TMPs-MTX) to treat advanced non-squamous non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE). Methods: This randomized, double-blind, placebo-controlled study was conducted at six hospitals in China from 20 July 2015 to 25 April 2019. Patients newly diagnosed with non-squamous NSCLC with MPE were randomly assigned to receive TMPs-MTX (group A) or saline (group B). Patients in both groups received pemetrexed (500 mg/m2 d1) and cisplatin (75 mg/m2 in total for d1-d2). Intrapleural infusion (50 mL saline containing 5 units of TMPs-MTX per perfusion, once every 48 hours, six total perfusions) was initiated on day 5 after pemetrexed-cisplatin chemotherapy. The primary outcome was the objective response rate (ORR) of MPE. Secondary outcomes included the ORR of target lesions, progression-free survival (PFS), overall survival (OS), toxicity, and pleural fluid properties. Results: A total of 86 patients were enrolled in this study and randomly assigned to either group A or group B. Of these, 79 patients were evaluable for response. The ORR of MPE in group A was significantly higher than that in group B (82.50% vs. 58.97%, P = 0.0237). The ORR of target lesions was 25.64% in group A and 20.51% in group B (P = 0.5909), respectively. With a median follow-up time of 18.8 months, median PFS were 6.4 (95% CI, 4.5-12.3) months in group A and 7.3 (95% CI, 6.1-10.4) months in group B (P = 0.6893), and median OS were 19.9 (95% CI, 17.1-28.5) months and 17.5 (95% CI, 11.6-25.0) months (P = 0.4500), respectively. The incidence rates of adverse events were similar in the two groups. The most common treatment-related adverse events were chemotherapy-induced toxicities, including fever, gastrointestinal reactions, hepatic dysfunction, and leukopenia. Conclusion: Intrapleural infusion of TMPs-MTX combined with pemetrexed-cisplatin chemotherapy is safe and effective against MPE in patients with advanced non-squamous NSCLC. Clinical trial registration: http://www.chictr.org.cn (ChiCTR-ICR-15006304).

Liver X receptors agonist T0901317 exerts ferroptosis sensitization in cancer.

Numerous studies have confirmed the anticancer effects of ferroptosis on a wide range of tumors, specifically in providing new perspectives for tackling drug resistance and treating refractory tumors. Notably, mechanisms of improving tumor susceptibility to ferroptosis have been a focus of current research. This study discovered that co-treatment of LXRS agonist T0901317 and ferroptosis inducers (FINs) significantly inhibited the proliferation of cancer cells, this inhibition effect could be reversed by specific inhibitors of ferroptosis and accompanied by elevated lipid peroxides. Glutathione peroxidase 4 (GPX4) regulates T0901317 induced ferroptotic sensitization, and its overexpression dramatically reverses the joint anticancer effect of T0901317 and FINs. Furthermore, xenograft model results highly confirmed the ferroptotic sensitization effect of T0901317 in vivo. In summary, our findings indicate that drug combination and ferroptosis induction strategies provide novel options for cancer therapy.

Localized Degradation of Neutrophil Extracellular Traps by Photoregulated Enzyme Delivery for Cancer Immunotherapy and Metastasis Suppression.

Extrusion of neutrophil extracellular traps (NETs), a fundamental host innate immune defense against pathogens, has recently been linked to cancer resistance to immunotherapy and distant metastasis. These findings highlight interesting areas of cancer-elicited inflammation and potential therapeutic strategies. Disrupting existing NETs with DNase I has been proved to enhance the therapeutic efficacy of tumor immunotherapy and attenuate metastatic spread. However, systemic biodistribution of DNase I raises safety issues, potentially impairing host defense against infection. Hence, tumor-specific delivery and metastatic niche-targeted effects are attractive options for localized degradation of NETs. We have engineered a nanoplatform with a plasmonic gold blackbody (AuPB) core with broad-spectrum photo activity and a mesoporous polydopamine (mPDA) shell for efficient loading and photoregulated release of DNase I. The on-demand released DNase I triggered by the second near-infrared (NIR-II) light irradiation breaks the "NET-mediated physical barrier", thereby increasing the contact of immune cytotoxic cells with tumor cells in living mice and sensitizing immune checkpoint therapy of primary colorectal cancer (CRC). Moreover, the deposition and light-controlled cargo release from systemically delivered AuPB@mPDA carriers in liver, the most frequent site of CRC metastasis, abolished NET-mediated capture of circulating tumor cells and hence metastatic seeding. Our findings indicate that the localized, light-regulated release of DNase I by photoactive carriers in the NIR-II window represent a translational route for immune-mediated tumor regression and metastasis inhibition.

Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement.

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.

Synthesis of Monodisperse ZIF-67@CuSe@PVP Nanoparticles for pH-Responsive Drug Release and Photothermal Therapy.

In recent years, the combination treatment of chemotherapy and photothermal therapy (PTT) has emerged as an efficient approach to improve anticancer activity. Here, we combine zeolitic imidazolate framework-67 (ZIF-67) and CuSe to build a multifunctional therapeutic platform (ZIF-67@CuSe@PVP) with an efficient chemo-photothermal therapy for cancer treatment. ZIF-67@CuSe@PVP nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis, Fourier transform infrared (FT-IR), and nitrogen adsorption-desorption isotherms. These nanoparticles exhibited excellent pH-responsive doxorubicin hydrochloride (DOX) releases due to the decomposition of ZIF-67 and excellent photothermal conversion efficiency (36%) without apparent deterioration during three cycles. In vivo biodistribution evaluation revealed the passive tumor-targeting ability of ZIF-67@CuSe@PVP@DOX via the enhanced permeability and retention (EPR) effect. Both in vitro and in vivo data demonstrated excellent anticancer efficacy of ZIF-67@CuSe@PVP in tumor-bearing mice. This multifunctional therapeutic platform could have certain clinical application potential.

LINC01140 promotes the progression and tumor immune escape in lung cancer by sponging multiple microRNAs.

BACKGROUND: Long intergenic non-protein coding RNA 1140 (LINC01140), a long non-coding RNA, is highly expressed in various cancers; however, its biological functions in lung cancer (LC) progression and immune escape are still unclear. METHODS: Here, to elucidate LINC01140 function, 79 paired LC and paracancerous tissues were collected. LINC01140 expression levels were determined using fluorescence in situ hybridization and qPCR analysis. Cell counting kit-8 (CCK-8) assay and transwell assays were performed. The interaction between microRNAs (miRNAs) and LINC01140 was confirmed using an RNA immunoprecipitation assay. Cytokine-induced killer (CIK) cell phenotypes were analyzed by flow cytometry. Cytokine secretion levels were determined by ELISA. CIK cytotoxicity was assessed by measuring lactate dehydrogenase release. Besides, xenograft tumor mouse models were used to unveil the in vivo function of LINC01140. RESULTS: We found that LINC01140 was highly expressed in human LC tissues and cell lines. High LINC01140 levels were associated with poor survival in patients with LC. LINC01140 upregulation promoted the proliferation, migration, and invasion of LC cells through direct interaction with miR-33a-5p and miR-33b-5p, thereby contributing to c-Myc expression and also inhibited cisplatin-induced cell apoptosis. In subcutaneous tumor xenograft mice, LINC01140 knockdown markedly reduced tumor growth and lung metastasis. Additionally, LINC01140 directly repressed miR-377-3 p and miR-155-5 p expression levels, resulting in the upregulation of their common downstream target programmed death-ligand 1 (PD-L1), a crucial target in LC immunotherapy. Notably, we proved that LINC01140 knockdown, along with CIK administration, suppressed the growth of subcutaneous LC xenografts by decreasing PD-L1 expression in severe combined immunodeficient mice. CONCLUSIONS: Taken together, LINC01140 overexpression protects c-Myc and PD-L1 mRNA from miRNA-mediated inhibition and contributes to the proliferation, migration, invasion, and immune escape of LC cells. These results provide a theoretical basis that LINC01140 is a promising target for LC treatment.

Salvage surgery following downstaging of advanced non-small cell lung cancer by targeted therapy.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) accounts for a high proportion of lung cancer cases. Targeted therapy improve the survival in these patients, but acquired drug resistance will inevitably occur. If tumor downstaging is achieved after targeted therapy, could surgical resection before drug resistance improve clinical benefits for patients with advanced NSCLC? Here, we conducted a clinical trial showing that for patients with advanced driver gene mutant NSCLC who did not progress after targeted therapy, salvage surgery (SS) could improve progression-free survival (PFS). Herein, we retrospectively reviewed our former clinical trial and thoracic cancer database in our medical institutions. METHODS: We identified patients with advanced driver gene mutant NSCLC treated with targeted therapy plus SS or targeted therapy alone in our former clinical trial and our thoracic cancer database from July 2016 to July 2019. PFS was compared between the targeted therapy plus SS group and the targeted therapy only group using the log-rank test. RESULTS: We identified 73 patients with driver gene mutant NSCLC who were treated with targeted therapy and 18 treated with targeted therapy plus SS.Among the 18 patients treated with targeted therapy plus SS, there were no obvious perioperative complications and deaths. Targeted therapy followed by SS resulted in a significantly longer PFS compared with targeted therapy alone (23.4 months VS 12.9 months, p = 0.0004). CONCLUSIONS: Salvage surgery after tumor downstaging is a promising therapeutic strategy for some patients with advanced (stage IIIB-IV) NSCLC and may offer a new therapeutic option for multidisciplinary comprehensive treatment of lung cancer.

Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation.

Among the various immunological and non-immunological tumor-promoting activities of myeloid-derived suppressor cells (MDSCs), their immunosuppressive capacity remains a key hallmark. Effort in the past decade has provided us with a clearer view of the suppressive nature of MDSCs. More suppressive pathways have been identified, and their recognized targets have been expanded from T cells and natural killer (NK) cells to other immune cells. These novel mechanisms and targets afford MDSCs versatility in suppressing both innate and adaptive immunity. On the other hand, a better understanding of the regulation of their development and function has been unveiled. This intricate regulatory network, consisting of tumor cells, stromal cells, soluble mediators, and hostile physical conditions, reveals bi-directional crosstalk between MDSCs and the tumor microenvironment. In this article, we will review available information on how MDSCs exert their immunosuppressive function and how they are regulated in the tumor milieu. As MDSCs are a well-established obstacle to anti-tumor immunity, new insights in the potential synergistic combination of MDSC-targeted therapy and immunotherapy will be discussed.